Ischemia is a restriction in blood supply to body organs, tissues, or body parts, causing eventually irreversible damage with necrosis of cells and tissues. In particular, the brain and the heart are body organs that are most susceptible to shortage of blood flow. When ischemia occurs in tissues caused by, for example, stroke or head injury, processes called ischemic cascade are caused and brain tissues are permanently damaged.
A cerebral infarction is caused by blockage or rupture of a blood vessel that supplies blood to the brain, which results in local damage of a brain, and is commonly called a “stroke.” Stroke symptoms include, for example, hemiplegia, sensory disorders, language disorders, dysphonia, visual acuity and visual field disorders, diplopia, headache, dizziness, loss of consciousness, a vegetative state, and dementia. Strokes can be classified into two categories: ischemic and hemorrhagic. Ischemic strokes (80 to 85%) are those that are caused by completely blocked blood vessels or severely narrowed blood vessels of the brain, which can lead to insufficient blood flow to tissues. Hemorrhagic strokes (15 to 20%) are those that are caused by hemorrhaging, which can lead to functional loss of brain cells. Stroke is the second most frequent cause of death in Korea, and the third most frequent cause of death worldwide. Since about 50% or more of stroke survivors may have some type of disability, patients and caregivers have social burdens.
In ischemic strokes, which account for most strokes, a patient's prognosis may be mostly determined depending on clinical progress of an acute phase (within 7 days) or a subacute phase (within 4 weeks). Recanalization treatment is performed to resupply blood flow such that brain tissues of ischemic penumbrae, which are physiological marks of acute phase treatment in ischemic strokes, function again. However, it is currently known that recanalization therapy needs to be performed within 4.5 hours after the onset of symptoms with an intravenous injection or within 6 hours after the onset of symptoms with an intraarterial injection in order to improve the patient's prognosis. However, stroke patients around the world are rarely identified on time and treated with appropriate recanalization in an emergency room. Therefore, since most patients with acute ischemic strokes are not appropriately managed, safe, effective, and new therapy for acute phase patients is necessary.
Meanwhile, although ischemic cardiovascular diseases or ischemic peripheral vascular diseases, which are ischemic diseases within tissues, have a relatively longer time window than those of the brain, there are still many patients who miss timely treatments and do not receive appropriate care. Even when reperfusion is successfully performed within a time window after ischemic diseases occur in cardiac, brain, and peripheral tissues, paradoxically, in some cases, tissue damages further occur. This is called a reperfusion injury. It is known that such reperfusion injury easily occurs when a blood vessel is suddenly blocked rather than blocked slowly, when tissues have large ischemic lesions, and when a time of blood vessel blockage is longer. Therefore, when such injuries occur, since tissue damage further occurs, a reperfusion operation or therapy may often lead to a poor prognosis.
Ischemic diseases such as cerebral infarctions, myocardial infarctions, and peripheral arterial obstructive diseases are generally caused by shortage of blood supply, which eventually results in irreversible damage to cells constituting organs.
Up to now, in order to treat excitotoxicity, inflammation, and oxidative stress occurring in an early stage of the ischemic cascade, that is, a destructive phase of tissues, neuroprotective drugs have been developed, on which preclinical studies and clinical studies have been conducted. However, no significant effects on the human body have been found yet.
In addition to an acute phase stroke, in chronic obstructive ischemic cerebrovascular diseases (including moyamoya disease), therapy for improving intracranial blood flow has been developed using anastomosis in which a normal lateral intracranial blood vessel and an abnormal intracranial blood vessel are attempted to be connected. Such vascular anastomosis is divided into two categories depending on treatment methods: direct and indirect. In direct vascular anastomosis, intra- or extra-cranial blood vessels are directly connected. In indirect vascular anastomosis, intra- or extra-cranial blood vessels are not directly connected. In direct vascular anastomosis, an extra-cranial blood vessel is dissected, and then a cranium is disruptiond, and an abnormal intracranial blood vessel is found and connected. In indirect vascular anastomosis, procedures are the same as above, but intra- or extra-cranial blood vessels are not directly connected. Therefore, a long operation time under general anesthesia, and skilled professionals are necessary. Particularly, the direct vascular anastomosis is highly dependent on surgeons, and thus even trustworthy medical institutions have reported postoperative cerebral infarctions in about 21% of cases and a mortality rate of about 9%. The indirect vascular anastomosis is a relatively simpler operation than the direct vascular anastomosis. However, due to premises of postoperative neovascularization, it may be applied only to pediatric patients who have better cerebral neovascularization environments and conditions than adults. In addition, although the indirect vascular anastomosis is a relatively simpler operation than the direct vascular anastomosis, operation side effects still occur and about 15% of postoperative patients have side effects such as cerebral infarctions. Accordingly, the anastomosis has been difficult to attempt in acute phase stroke treatment. Alternatively, a multiple burr-hole operation is safe therapy having few complications, has a short operation time under local anesthesia, is non-dependent on surgeons, and a clinician may monitor and manage changes in a patient's condition during the procedure.
Meanwhile, it has been reported that neovascularization is induced from a meningeal artery and a moyamoya blood vessel disappears when the multiple burr-hole operation is performed on a plurality of adult moyamoya patients (J Korean Neurosurg Soc 35:17-22, 2004, Ko Youngsam et al.). However, since this operation was not performed in acute phase stroke patients, and neovascularization was not induced in all patients, this operation is not being actively applied worldwide. Korea Patent No. 10-0774827 discloses that when erythropoietin is locally administered in ischemic brain tissues, significant neuroprotective effects occur, and thus an area of permanently damaged brain tissues is decreased. However, this patent literature mentions only the neuroprotective effects. In addition, US Patent Publication No. 2010-0247452 discloses that erythropoietin improves differentiation and adhesion of endothelial progenitor cells, and thus neovascularization may be induced from tissues or organs in which a blood vessel is formed or from which a blood vessel formation stimulus is released. However, this patent literature does not mention or provide a concept of a physical barrier of a living body.